δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy

Anne-Fleur van Rootselaar; Alexander J Groffen; Boukje de Vries; Petra M C Callenbach; Gijs W E Santen; Stephany Koelewijn; Lisanne S Vijfhuizen; Arthur Buijink; Marina A J Tijssen; Arn M J M van den Maagdenberg

doi:10.1212/WNL.0000000000004709

δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy

Anne-Fleur van Rootselaar, Alexander J Groffen, Boukje de Vries, Petra M C Callenbach, Gijs W E Santen, Stephany Koelewijn, Lisanne S Vijfhuizen, Arthur Buijink, Marina A J Tijssen, Arn M J M van den Maagdenberg

Functional Genomics

Research output: Contribution to Journal › Article › Academic › peer-review

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Abstract

OBJECTIVE: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE).

METHODS: We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human δ-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain.

RESULTS: We identified a missense mutation, p.Glu1044Lys, in the CTNND2 gene that cosegregated with the FCMTE phenotype. The knock-down of Ctnnd2 in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild-type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE.

CONCLUSIONS: We propose CTNND2 as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE.

Original language	English
Pages (from-to)	2341-2350
Number of pages	10
Journal	Neurology
Volume	89
Issue number	23
DOIs	https://doi.org/10.1212/WNL.0000000000004709
Publication status	Published - 5 Dec 2017

Funding

This study was financially supported by the Centre of Medical System Biology established by the Netherlands Genomics Initiative/Netherlands Organisation for Scientific Research to A.M.J.M.v.d.M.

Funders	Funder number
Gossweiler Foundation
Merz
Stichting Wetenschapsfonds Dystonie Vereniging
Medtronic
Actelion Pharmaceuticals
Allergan
Fonds NutsOhra
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Prinses Beatrix Spierfonds
Ipsen

Keywords

Adult
Aged
Aged, 80 and over
Animals
Catenins
Epilepsies, Myoclonic
Essential Tremor
Exome
Family
Female
Humans
Journal Article
Male
Mice
Mice, Transgenic
Middle Aged
Mutation, Missense
Neurons
Pedigree
Purkinje Cells
RNA, Small Interfering
Young Adult

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1212/WNL.0000000000004709

δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsyFinal published version, 1.2 MBLicence: Article 25fa Dutch Copyright Act

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title = "δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy",

abstract = "OBJECTIVE: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE).METHODS: We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human δ-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain.RESULTS: We identified a missense mutation, p.Glu1044Lys, in the CTNND2 gene that cosegregated with the FCMTE phenotype. The knock-down of Ctnnd2 in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild-type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE.CONCLUSIONS: We propose CTNND2 as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE.",

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author = "\{van Rootselaar\}, Anne-Fleur and Groffen, \{Alexander J\} and \{de Vries\}, Boukje and Callenbach, \{Petra M C\} and Santen, \{Gijs W E\} and Stephany Koelewijn and Vijfhuizen, \{Lisanne S\} and Arthur Buijink and Tijssen, \{Marina A J\} and \{van den Maagdenberg\}, \{Arn M J M\}",

note = "{\textcopyright} 2017 American Academy of Neurology.",

year = "2017",

month = dec,

day = "5",

doi = "10.1212/WNL.0000000000004709",

language = "English",

volume = "89",

pages = "2341--2350",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "23",

}

TY - JOUR

T1 - δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy

AU - van Rootselaar, Anne-Fleur

AU - Groffen, Alexander J

AU - de Vries, Boukje

AU - Callenbach, Petra M C

AU - Santen, Gijs W E

AU - Koelewijn, Stephany

AU - Vijfhuizen, Lisanne S

AU - Buijink, Arthur

AU - Tijssen, Marina A J

AU - van den Maagdenberg, Arn M J M

PY - 2017/12/5

Y1 - 2017/12/5

N2 - OBJECTIVE: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE).METHODS: We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human δ-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain.RESULTS: We identified a missense mutation, p.Glu1044Lys, in the CTNND2 gene that cosegregated with the FCMTE phenotype. The knock-down of Ctnnd2 in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild-type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE.CONCLUSIONS: We propose CTNND2 as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE.

AB - OBJECTIVE: To identify the causative gene in a large Dutch family with familial cortical myoclonic tremor and epilepsy (FCMTE).METHODS: We performed exome sequencing for 3 patients of our FCMTE family. Next, we performed knock-down (shRNA) and rescue experiments by overexpressing wild-type and mutant human δ-catenin (CTNND2) proteins in cortical mouse neurons and compared the results with morphologic abnormalities in the postmortem FCMTE brain.RESULTS: We identified a missense mutation, p.Glu1044Lys, in the CTNND2 gene that cosegregated with the FCMTE phenotype. The knock-down of Ctnnd2 in cultured cortical mouse neurons revealed increased neurite outgrowth that was rescued by overexpression of wild-type, but not mutant, CTNND2 and was reminiscent of the morphologic abnormalities observed in cerebellar Purkinje cells from patients with FCMTE.CONCLUSIONS: We propose CTNND2 as the causal gene in FCMTE3. Functional testing of the mutant protein revealed abnormal neuronal sprouting, consistent with the abnormal cerebellar Purkinje cell morphology in patients with FCMTE.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Animals

KW - Catenins

KW - Epilepsies, Myoclonic

KW - Essential Tremor

KW - Exome

KW - Family

KW - Female

KW - Humans

KW - Journal Article

KW - Male

KW - Mice

KW - Mice, Transgenic

KW - Middle Aged

KW - Mutation, Missense

KW - Neurons

KW - Pedigree

KW - Purkinje Cells

KW - RNA, Small Interfering

KW - Young Adult

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U2 - 10.1212/WNL.0000000000004709

DO - 10.1212/WNL.0000000000004709

M3 - Article

C2 - 29127138

SN - 0028-3878

VL - 89

SP - 2341

EP - 2350

JO - Neurology

JF - Neurology

IS - 23

ER -

δ-Catenin (CTNND2) missense mutation in familial cortical myoclonic tremor and epilepsy

Abstract

Funding

Keywords

UN SDGs

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